The present invention relates to vitamin D compounds, and more particularly to the synthesis of an A-ring synthon used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis.
The natural hormone, 1xcex1,25-dihydroxyvitamin D3 and its analog in ergosterol series, i.e. 1xcex1,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1xcex1-hydroxyvitamin D3, 1xcex1-hydroxyvitamin D2, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases.
The discovery of the hormonally active form of vitamin D3, 1xcex1,25-dihydroxyvitamin D3 (1xcex1,25-(OH)2D3 or calcitriol) has greatly stimulated research into its physiology and chemistry. As previously noted, it has been established that 1xcex1,25-(OH)2D3 not only regulates the mineral metabolism in animals and humans, but also exerts potent effects upon cell proliferation and cellular differentiation. Therefore, the chemistry of vitamin D has been recently focused on the design and synthesis of analogs that can exert selective biological actions.
Recently, a class of vitamin D analogs has been discovered, i.e. the so called 19-nor-vitamin D compounds, which are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1xcex1,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Different methods of synthesis of such 19-nor-vitamin D analogs have been described. See for example Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), DeLuca et al., U.S. Pat. No. 5,086,191, and DeLuca et al U.S. Pat. No. 5,936,133.
In one particularly advantageous method, the preparation of various 19-nor-vitamin D compounds can be accomplished by the condensation of a bicyclic Windaus-Grundmann type ketone having the desired side chain structure with an A-ring phosphine oxide to the corresponding 19-nor vitamin D analog followed by deprotection, particularly at C-1 and C-3 in the latter compounds. One method of preparing the required A-ring phosphine oxides is to transform a methyl ester obtained from quinic acid into the desired A-ring synthon in accordance with the synthesis set forth in DeLuca et al U.S. Pat. No. 5,936,133. It is, however, desirable to provide an alternate method for preparing such A-ring phosphine oxides.
The present invention provides a new method for the synthesis of an A-ring synthon phosphine oxide used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis. The new method prepares the phosphine oxide from (D)-glucose.
The A-ring synthon phosphine oxide to be prepared is represented by the following structure 
where the wavy line indicates a stereochemical center so that the phosphine oxide substituent may have either the R or S configuration, and may thus be obtained as a mixture of two isomers. Each of R3, R4 and R5 may independently be selected from a hydroxy protecting group, but preferably R3 and R5 are both a t-butyldimethylsilyl hydroxy protecting group (abbreviated xe2x80x9cTBSxe2x80x9d) and R4 is a trimethylsilyl hydroxy protecting group (abbreviated xe2x80x9cTMSxe2x80x9d).
Preferably, the method of making the phosphine oxide comprises the steps of:
converting D-glucose having the structure 
to a 2-deoxy-glucose derivative having the structure 
where R1 is an alkyl group;
iodinating the 2-deoxy-glucose derivative to form a 5-iodinated derivative having the structure 
eliminating the iodine substituent of said 5-iodinated derivative to form a 1-ether derivative having the structure 
reducing the 1-ether derivative to form a 1-alcohol derivative having the structure 
converting the 1-alcohol derivative to a 1-protected derivative having the structure 
where R2 is a hydroxy protecting group;
reducing the 1-protected derivative with a metal hydride to form a 5-alcohol derivative having the structure 
benzylating the 5-alcohol derivative to form a benzylated derivative having the structure 
hydrolyzing the benzyl derivative to form a 1-hydroxyl derivative having the structure 
oxidizing the 1-hydroxyl derivative to form a 1-ketone derivative having the structure 
converting the 1-ketone derivative to a 3,4,5-protected derivative having the structure 
where R3, R4 and R5 are each independently a hydroxy-protecting group;
condensing the 3,4,5-protected derivative to an ester derivative having the structure 
where R6 is an alkyl group;
reducing the ester derivative with a metal hydride to form a 3,4,5-protected-1-alcohol derivative having the structure 
and converting the 3,4,5-protected-1-alcohol to a phosphine oxide having the structure 
Alternate methods of converting D-glucose to the 2-deoxy-glucose derivative are illustrated in FIGS. 1 and 2.